The basic goals of this research effort are to understand how signaling protein kinases like RSK and ERK, contribute to normal biological processes such as the regulation of cell migration, growth, proliferation and survival. Importantly, we also wish to determine how when improperly regulated, for example, following activation of a proto-oncogene product like the small G-protein Ras, these protein kinases contribute to disease phenotypes. The ultimate goal of this research is to identify potential targets for biomarker development and disease intervention. The basic aims of this proposal are to characterize RSK regulation, interacting partners and downstream effectors. We utilize various molecular, cell biological and biochemical approaches to accomplish this analysis. With this multifaceted approach, our goal is to continue to investigate how RSK signaling contributes to the biology associated with normal cell proliferation and when improperly regulated, carcinogenesis. In addition, we propose to carefully characterize ERK signaling, not only to RSK, but also to a second category of ERK effectors based on distinct interaction motifs. Again using a variety of experimental approaches, our experimental observations have proved to be extremely enlightening. We aim to continue to investigate a unique mechanism for ERK signaling to distinct biological effectors that can provide a molecular cell fate sensing mechanism for monitoring and differentially responding to/subtle changes in ERK/RSK signal strength, location and duration. In addition, this arm of ERK signaling is intimately linked to processes contributing to cancer cell migration, survival and metastasis. Activating mutations in the Ras protbbncoprotein are observed is greater than 30% of human cancers and the~Ras:MAP kinase pathway is inappropriately activated in greater than 70% of aggressive1 human cancers such as colon, pancreatic,'lung, breast, ovary, skin, braih and others. Our current understanding of this pathway8 has already led to the development of some potential'anti-cancer therapies:that are just entering cliriicalftriails. Additional potential drug targets must be discoveredand hew drugs^toJnhibit this pathway are desperately needed/The proposed studies are leading'to the identification of new candidate drug-targetsas well aspotential targets for the development of needed bibmarkers that will be used to quickly determine if a patients'cancer has this pathway activated. Eventually, this knowledge will result in the rationale design of targeted therapies that will be both efficacious and less toxic to the patient.